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Keywords = damaged DNA-binding protein 1

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11 pages, 775 KiB  
Review
Cooperation Between Aflatoxin-Induced p53 Aberrations and Hepatitis B Virus in Hepatocellular Carcinoma
by Carolina Moreno-León and Francisco Aguayo
J. Xenobiot. 2025, 15(4), 96; https://doi.org/10.3390/jox15040096 - 20 Jun 2025
Viewed by 570
Abstract
Hepatocellular carcinoma (HCC) imposes a significant burden on global public health. Exposure to aflatoxins, potent mycotoxins produced by Aspergillus fungi contaminating staple foods, and chronic hepatitis B virus (HBV) infection are major etiological factors, especially where they co-exist. This review examines the critical [...] Read more.
Hepatocellular carcinoma (HCC) imposes a significant burden on global public health. Exposure to aflatoxins, potent mycotoxins produced by Aspergillus fungi contaminating staple foods, and chronic hepatitis B virus (HBV) infection are major etiological factors, especially where they co-exist. This review examines the critical role of the p53 tumor suppressor pathway as a primary target and convergence point for the carcinogenic actions of aflatoxins and HBV. Aflatoxin B1 (AFB1), a Group 1 carcinogen, exerts significant genotoxicity, characteristically inducing a specific hotspot mutation (R249S) in the TP53 gene via DNA adduct formation, thereby compromising p53’s critical tumor suppressor functions. This R249S mutation is considered a molecular fingerprint of aflatoxin exposure. Concurrently, the HBV X protein (HBx) functionally inactivates wild-type p53 through direct binding and by promoting its degradation. The synergistic disruption of the p53 pathway, driven by AFB1-induced mutation and amplified by HBV-mediated functional inhibition, significantly enhances the risk of HCC development. This review addresses how aflatoxin exposure alters key aspects of p53 and how this damage interacts with HBV-mediated p53 suppression, providing crucial insights into hepatocarcinogenesis. The knowledge synthesized here underscores the importance of mitigating aflatoxin exposure alongside HBV control for effective HCC prevention and treatment strategies. Full article
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18 pages, 5795 KiB  
Article
C1QBP Modulates DNA Damage Response and Radiosensitivity in Hepatocellular Carcinoma by Regulating NF-κB Activity
by Haitao Zhou, Yanjin Wu, Jiahui Meng, Xiaotong Zhao, Yujia Hou, Qin Wang and Yang Liu
Int. J. Mol. Sci. 2025, 26(10), 4513; https://doi.org/10.3390/ijms26104513 - 9 May 2025
Viewed by 508
Abstract
C1QBP (Complement Component 1 Q Subcomponent-Binding Protein) plays a critical role in maintaining cellular metabolism, but its function in radiation-induced damage remains unclear. In this study, we generated C1QBP-deficient Huh-7 hepatocellular carcinoma (HCC) cells using CRISPR/Cas9 technology and observed that C1QBP deficiency significantly [...] Read more.
C1QBP (Complement Component 1 Q Subcomponent-Binding Protein) plays a critical role in maintaining cellular metabolism, but its function in radiation-induced damage remains unclear. In this study, we generated C1QBP-deficient Huh-7 hepatocellular carcinoma (HCC) cells using CRISPR/Cas9 technology and observed that C1QBP deficiency significantly enhanced radiation-induced damage, as indicated by reduced cell proliferation, impaired colony formation, and increased γ-H2AX foci, a marker of DNA double-strand breaks. Additionally, C1QBP deficiency resulted in elevated phosphorylation of key DNA damage response (DDR) molecules, ATM and CHK2, and caused pronounced S phase cell cycle arrest. Mechanistic investigations revealed that C1QBP modulates NF-κB nuclear activity via the AMPK signaling pathway. The loss of C1QBP reduced NF-κB nuclear translocation, further exacerbating radiation-induced damage. Reintroducing C1QBP alleviated DNA damage, enhanced cell proliferation, and improved survival following radiation exposure. These findings highlight the critical role of C1QBP in modulating HCC cells radiosensitivity and underscore its potential as a therapeutic target to enhance radiotherapy outcomes. Full article
(This article belongs to the Special Issue Radiation-Induced DNA Damage and Toxicity)
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35 pages, 5069 KiB  
Review
Small-Molecule Mitotic Inhibitors as Anticancer Agents: Discovery, Classification, Mechanisms of Action, and Clinical Trials
by Yazmin Salinas, Subhash C. Chauhan and Debasish Bandyopadhyay
Int. J. Mol. Sci. 2025, 26(7), 3279; https://doi.org/10.3390/ijms26073279 - 1 Apr 2025
Cited by 1 | Viewed by 1695
Abstract
Despite decades of research, cancer continues to be a disease of great concern to millions of people around the world. It has been responsible for a total of 609,820 deaths in the U.S. alone in 2023. Over the years, many drugs have been [...] Read more.
Despite decades of research, cancer continues to be a disease of great concern to millions of people around the world. It has been responsible for a total of 609,820 deaths in the U.S. alone in 2023. Over the years, many drugs have been developed to remove or reduce the disease’s impact, all with varying mechanisms of action and side effects. One class of these drugs is small-molecule mitotic inhibitors. These drugs inhibit cancer cell mitosis or self-replication, impeding cell proliferation and eventually leading to cell death. In this paper, small-molecule mitotic inhibitors are discussed and classified through their discovery, underlying chemistry, and mechanism(s) of action. The binding/inhibition of microtubule-related proteins, DNA damage through the inhibition of Checkpoint Kinase 1 protein, and the inhibition of mitotic kinase proteins are discussed in terms of their anticancer activity to provide an overview of a variety of mitotic inhibitors currently commercially available or under investigation, including those in ongoing clinical trial. Clinical trials for anti-mitotic agents are discussed to track research progress, gauge current understanding, and identify possible future prospects. Additionally, antibody–drug conjugates that use mitotic inhibitors as cytotoxic payloads are discussed as possible ways of administering effective anticancer treatments with minimal toxicity. Full article
(This article belongs to the Collection Feature Papers in Molecular Oncology)
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13 pages, 2428 KiB  
Article
Identification of Quantitative Trait Loci and Analysis of Novel Candidate Genes for Resistance to False Smut of Rice Based on SSR Molecular Markers
by Rongtao Fu, Liyu Zhao, Cheng Chen, Jian Wang, Yu Chen and Daihua Lu
Biomolecules 2025, 15(2), 186; https://doi.org/10.3390/biom15020186 - 28 Jan 2025
Cited by 2 | Viewed by 925
Abstract
Rice false smut (RFS), an emerging disease caused by the fungus Ustilaginoidea virens (Cooke), reduces rice grain yield and quality in rice-planting regions worldwide. The identification of the genes or quantitative trait loci (QTLs) associated with RFS resistance is vital to resistance breeding [...] Read more.
Rice false smut (RFS), an emerging disease caused by the fungus Ustilaginoidea virens (Cooke), reduces rice grain yield and quality in rice-planting regions worldwide. The identification of the genes or quantitative trait loci (QTLs) associated with RFS resistance is vital to resistance breeding and the mitigation of RFS damage. In this study, RFS resistance QTLs were located in the resistant variety IR77298-14-1-2::IRGC117374-1. A total of 4 RFS resistance QTLs were detected on rice chromosomes 1, 3, 5, and 12 in the F2 and F4 mapping populations using 119 polymorphic simple sequence repeat (SSR) molecular markers. Of these QTLs, qRFS3.01 and qRFS12.01-1 were repeatedly detected in both populations. Interestingly, QTL qRFS3.01 on chromosome 3 is a novel resistance locus that exhibited the largest phenotypic effect. These results suggest that SSR markers linked to qRFS3.01 are valuable for marker-assisted breeding for RFS resistance in rice. The prediction of putative candidate genes within qRFS3.01 revealed three resistance-related proteins containing an F-box domain, Myb-like DNA-binding domain, and kinase protein. In summary, our findings provide new QTLs/genes for resistance to RFS and will promote rice disease resistance through molecular-marker-assisted breeding. Full article
(This article belongs to the Collection Feature Papers in Molecular Genetics)
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17 pages, 1695 KiB  
Article
Interaction of DDB1 with NBS1 in a DNA Damage Checkpoint Pathway
by Hoe Eun Lim, Hee Jung Lim and Hae Yong Yoo
Int. J. Mol. Sci. 2024, 25(23), 13097; https://doi.org/10.3390/ijms252313097 - 5 Dec 2024
Cited by 1 | Viewed by 1161
Abstract
Various DNA damage checkpoint control mechanisms in eukaryotic cells help maintain genomic integrity. Among these, NBS1, a key component of the MRE11-RAD50-NBS1 (MRN) complex, is an essential protein involved in the DNA damage response (DDR). In this study, we discovered that DNA damage-binding [...] Read more.
Various DNA damage checkpoint control mechanisms in eukaryotic cells help maintain genomic integrity. Among these, NBS1, a key component of the MRE11-RAD50-NBS1 (MRN) complex, is an essential protein involved in the DNA damage response (DDR). In this study, we discovered that DNA damage-binding protein 1 (DDB1) interacts with NBS1. DDB1 is a DDR sensor protein found in UV-induced DNA replication blocks. Through pull-down and immunoprecipitation assays conducted in Xenopus egg extracts and human cell lines, we demonstrated a specific interaction between NBS1 and DDB1. DDB1 was also found to associate with several proteins that interact with NBS1, including DNA topoisomerase 2-binding protein 1 (TopBP1) and Mediator of DNA damage checkpoint protein 1 (MDC1). Notably, the interaction between DDB1 and NBS1 is disrupted in MDC1-depleted egg extracts, indicating that MDC1 is necessary for this interaction. Furthermore, the depletion of DDB1 leads to increased Chk1 activation upon DNA damage. These novel findings regarding the interaction between NBS1 and DDB1 provide new insights into how DDB1 regulates DNA damage pathways. Full article
(This article belongs to the Section Molecular Biology)
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23 pages, 4579 KiB  
Review
Mechanistic Insights into Influenza A Virus-Induced Cell Death and Emerging Treatment Strategies
by Yuling Sun and Kaituo Liu
Vet. Sci. 2024, 11(11), 555; https://doi.org/10.3390/vetsci11110555 - 10 Nov 2024
Cited by 2 | Viewed by 3940
Abstract
Influenza A virus (IAV) infection initiates a complex interplay of cell death modalities, including apoptosis, necroptosis, pyroptosis, and their integration, known as PANoptosis, which significantly impacts host immune responses and tissue integrity. These pathways are intricately regulated by viral proteins and host factors, [...] Read more.
Influenza A virus (IAV) infection initiates a complex interplay of cell death modalities, including apoptosis, necroptosis, pyroptosis, and their integration, known as PANoptosis, which significantly impacts host immune responses and tissue integrity. These pathways are intricately regulated by viral proteins and host factors, contributing to both viral clearance and pathogenesis-related tissue damage. This review comprehensively explores the molecular mechanisms underlying these cell death processes in influenza infection. We highlight the roles of key regulatory proteins, such as ZBP1 (Z-DNA binding protein 1) and RIPK3 (receptor-interacting protein kinase 3), in orchestrating these responses, emphasizing the dual roles of cell death in both antiviral defense and tissue injury. Furthermore, we discuss emerging therapeutic strategies targeting these pathways, aiming to enhance antiviral efficacy while minimizing collateral tissue damage. Future research should focus on targeted approaches to modulate cell death mechanisms, aiming to reduce tissue damage and improve clinical outcomes for patients with severe influenza. Full article
(This article belongs to the Special Issue Advances in Veterinary Clinical Microbiology)
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14 pages, 6226 KiB  
Article
Significance of P53-Binding Protein 1 as a Novel Molecular Histological Marker for Hypopharyngeal Squamous Neoplasms
by Hiroko Kawasaki-Inomata, Maiko Tabuchi, Kiyuu Norimatsu, Tetsuro Honda, Katsuya Matsuda, Keiichi Hashiguchi, Naoyuki Yamaguchi, Hideaki Nishi, Yoshihiko Kumai, Masahiro Nakashima, Hisamitsu Miyaaki, Kazuhiko Nakao and Yuko Akazawa
Cancers 2024, 16(17), 2987; https://doi.org/10.3390/cancers16172987 - 28 Aug 2024
Viewed by 1236
Abstract
The DNA damage response protein p53-binding protein 1 (53BP1) accumulates and forms foci at double-strand DNA breaks, indicating the extent of DNA instability. However, the potential role of 53BP1 as a molecular biomarker for hypopharyngeal squamous cell carcinoma (HPSCC) diagnosis remains unknown. Here, [...] Read more.
The DNA damage response protein p53-binding protein 1 (53BP1) accumulates and forms foci at double-strand DNA breaks, indicating the extent of DNA instability. However, the potential role of 53BP1 as a molecular biomarker for hypopharyngeal squamous cell carcinoma (HPSCC) diagnosis remains unknown. Here, we evaluated the potential of immunofluorescence-based analysis of 53BP1 expression to differentiate the histology of hypopharyngeal neoplasms. A total of 125 lesions from 39 surgically or endoscopically resected specimens from patients with HPSCC was histologically evaluated. 53BP1 expression in the nucleus was examined using immunofluorescence. The number of 53BP1 nuclear foci increased with the progression from non-tumorous to low-grade dysplasia, high-grade dysplasia, and squamous cell carcinoma. Unstable 53BP1 expression served as an independent factor for distinguishing lesions that required intervention. Colocalization of 53BP1 foci in proliferating cells, as assessed by Ki67, was increased in tumors ≥ 1000 µm in depth compared to those <1000 µm in depth at the tumor surface. Hence, the expression patterns of nuclear 53BP1 foci were associated with the progression of hypopharyngeal neoplasms. These findings suggest that 53BP1 could serve as an ancillary marker to support histological diagnosis and predict the factors that influence prognosis in patients with HPSCC. Full article
(This article belongs to the Section Cancer Biomarkers)
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19 pages, 4269 KiB  
Article
Visual Evidence for the Recruitment of Four Enzymes with RNase Activity to the Bacillus subtilis Replication Forks
by Rebecca Hinrichs and Peter L. Graumann
Cells 2024, 13(16), 1381; https://doi.org/10.3390/cells13161381 - 20 Aug 2024
Viewed by 1407
Abstract
Removal of RNA/DNA hybrids for the maturation of Okazaki fragments on the lagging strand, or due to misincorporation of ribonucleotides by DNA polymerases, is essential for all types of cells. In prokaryotic cells such as Escherichia coli, DNA polymerase 1 and RNase [...] Read more.
Removal of RNA/DNA hybrids for the maturation of Okazaki fragments on the lagging strand, or due to misincorporation of ribonucleotides by DNA polymerases, is essential for all types of cells. In prokaryotic cells such as Escherichia coli, DNA polymerase 1 and RNase HI are supposed to remove RNA from Okazaki fragments, but many bacteria lack HI-type RNases, such as Bacillus subtilis. Previous work has demonstrated in vitro that four proteins are able to remove RNA from RNA/DNA hybrids, but their actual contribution to DNA replication is unclear. We have studied the dynamics of DNA polymerase A (similar to Pol 1), 5′->3′ exonuclease ExoR, and the two endoribonucleases RNase HII and HIII in B. subtilis using single-molecule tracking. We found that all four enzymes show a localization pattern similar to that of replicative DNA helicase. By scoring the distance of tracks to replication forks, we found that all four enzymes are enriched at DNA replication centers. After inducing UV damage, RNase HIII was even more strongly recruited to the replication forks, and PolA showed a more static behavior, indicative of longer binding events, whereas RNase HII and ExoR showed no response. Inhibition of replication by 6(p hydroxyphenylazo)-uracil (HPUra) demonstrated that both RNase HII and RNase HIII are directly involved in the replication. We found that the absence of ExoR increases the likelihood of RNase HIII at the forks, indicating that substrate availability rather than direct protein interactions may be a major driver for the recruitment of RNases to the lagging strands. Thus, B. subtilis replication forks appear to be an intermediate between E. coli type and eukaryotic replication forks and employ a multitude of RNases, rather than any dedicated enzyme for RNA/DNA hybrid removal. Full article
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20 pages, 6027 KiB  
Article
Promising Effects of Novel Supplement Formulas in Preventing Skin Aging in 3D Human Keratinocytes
by Angela Punzo, Matteo Perillo, Alessia Silla, Marco Malaguti, Silvana Hrelia, Diogo Barardo, Cristiana Caliceti and Antonello Lorenzini
Nutrients 2024, 16(16), 2770; https://doi.org/10.3390/nu16162770 - 20 Aug 2024
Cited by 1 | Viewed by 4908
Abstract
Dietary intervention is considered a safe preventive strategy to slow down aging. This study aimed to evaluate the protective effects of a commercially available supplement and six simpler formulations against DNA damage in 3D human keratinocytes. The ingredients used are well known and [...] Read more.
Dietary intervention is considered a safe preventive strategy to slow down aging. This study aimed to evaluate the protective effects of a commercially available supplement and six simpler formulations against DNA damage in 3D human keratinocytes. The ingredients used are well known and were combined into various formulations to test their potential anti-aging properties. Firstly, we determined the formulations’ safe concentration by evaluating cytotoxicity and cell viability through spectrophotometric assays. We then examined the presence of tumor p53 binding protein 1 and phosphorylated histone H2AX foci, which are markers of genotoxicity. The foci count revealed that a 24-h treatment with the supplement did not induce DNA damage, and significantly reduced DNA damage in cells exposed to neocarzinostatin for 2 h. Three of the simpler formulations showed similar results. Moreover, the antioxidant activity was tested using a recently developed whole cell-based chemiluminescent bioassay; results showed that a 24-h treatment with the supplement and three simpler formulations significantly reduced intracellular H2O2 after pro-oxidant injury, thus suggesting their possible antiaging effect. This study’s originality lies in the use of a 3D human keratinocyte cell model and a combination of natural ingredients targeting DNA damage and oxidative stress, providing a robust evaluation of their anti-aging potential. Full article
(This article belongs to the Section Nutrition and Public Health)
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13 pages, 13343 KiB  
Article
Nanoscale Interaction of Endonuclease APE1 with DNA
by Sridhar Vemulapalli, Mohtadin Hashemi, Yingling Chen, Suravi Pramanik, Kishor K. Bhakat and Yuri L. Lyubchenko
Int. J. Mol. Sci. 2024, 25(10), 5145; https://doi.org/10.3390/ijms25105145 - 9 May 2024
Viewed by 1528
Abstract
Apurinic/apyrimidinic endonuclease 1 (APE1) is involved in DNA repair and transcriptional regulation mechanisms. This multifunctional activity of APE1 should be supported by specific structural properties of APE1 that have not yet been elucidated. Herein, we applied atomic force microscopy (AFM) to characterize the [...] Read more.
Apurinic/apyrimidinic endonuclease 1 (APE1) is involved in DNA repair and transcriptional regulation mechanisms. This multifunctional activity of APE1 should be supported by specific structural properties of APE1 that have not yet been elucidated. Herein, we applied atomic force microscopy (AFM) to characterize the interactions of APE1 with DNA containing two well-separated G-rich segments. Complexes of APE1 with DNA containing G-rich segments were visualized, and analysis of the complexes revealed the affinity of APE1 to G-rich DNA sequences, and their yield was as high as 53%. Furthermore, APE1 is capable of binding two DNA segments leading to the formation of loops in the DNA–APE1 complexes. The analysis of looped APE1-DNA complexes revealed that APE1 can bridge G-rich segments of DNA. The yield of loops bridging two G-rich DNA segments was 41%. Analysis of protein size in various complexes was performed, and these data showed that loops are formed by APE1 monomer, suggesting that APE1 has two DNA binding sites. The data led us to a model for the interaction of APE1 with DNA and the search for the specific sites. The implication of these new APE1 properties in organizing DNA, by bringing two distant sites together, for facilitating the scanning for damage and coordinating repair and transcription is discussed. Full article
(This article belongs to the Collection Feature Papers in Molecular Nanoscience)
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14 pages, 1318 KiB  
Review
Fragile X Messenger Ribonucleoprotein Protein and Its Multifunctionality: From Cytosol to Nucleolus and Back
by Mohamed S. Taha and Mohammad Reza Ahmadian
Biomolecules 2024, 14(4), 399; https://doi.org/10.3390/biom14040399 - 26 Mar 2024
Cited by 3 | Viewed by 3189
Abstract
Silencing of the fragile X messenger ribonucleoprotein 1 (FMR1) gene and a consequent lack of FMR protein (FMRP) synthesis are associated with fragile X syndrome, one of the most common inherited intellectual disabilities. FMRP is a multifunctional protein that is involved [...] Read more.
Silencing of the fragile X messenger ribonucleoprotein 1 (FMR1) gene and a consequent lack of FMR protein (FMRP) synthesis are associated with fragile X syndrome, one of the most common inherited intellectual disabilities. FMRP is a multifunctional protein that is involved in many cellular functions in almost all subcellular compartments under both normal and cellular stress conditions in neuronal and non-neuronal cell types. This is achieved through its trafficking signals, nuclear localization signal (NLS), nuclear export signal (NES), and nucleolar localization signal (NoLS), as well as its RNA and protein binding domains, and it is modulated by various post-translational modifications such as phosphorylation, ubiquitination, sumoylation, and methylation. This review summarizes the recent advances in understanding the interaction networks of FMRP with a special focus on FMRP stress-related functions, including stress granule formation, mitochondrion and endoplasmic reticulum plasticity, ribosome biogenesis, cell cycle control, and DNA damage response. Full article
(This article belongs to the Section Biomacromolecules: Proteins, Nucleic Acids and Carbohydrates)
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16 pages, 7041 KiB  
Article
Exploring Transcriptional Regulation of Beta Cell SASP by Brd4-Associated Proteins and Cell Cycle Control Protein p21
by Jasmine Manji, Jasmine Pipella, Gabriel Brawerman and Peter J. Thompson
Epigenomes 2024, 8(1), 10; https://doi.org/10.3390/epigenomes8010010 - 6 Mar 2024
Cited by 1 | Viewed by 3353
Abstract
Type 1 diabetes (T1D) is a metabolic disease resulting from progressive autoimmune destruction of insulin-producing pancreatic beta cells. Although the majority of beta cells are lost in T1D, a small subset undergoes senescence, a stress response involving growth arrest, DNA damage response, and [...] Read more.
Type 1 diabetes (T1D) is a metabolic disease resulting from progressive autoimmune destruction of insulin-producing pancreatic beta cells. Although the majority of beta cells are lost in T1D, a small subset undergoes senescence, a stress response involving growth arrest, DNA damage response, and activation of a senescence-associated secretory phenotype (SASP). SASP in beta cells of the nonobese diabetic (NOD) mouse model of T1D and primary human islets is regulated at the level of transcription by bromodomain extra-terminal (BET) proteins, but the mechanisms remain unclear. To explore how SASP is transcriptionally regulated in beta cells, we used the NOD beta cell line NIT-1 to model beta cell SASP and identified binding partners of BET protein Brd4 and explored the role of the cyclin-dependent kinase inhibitor p21. Brd4 interacted with a variety of proteins in senescent NIT-1 cells including subunits of the Ino80 chromatin remodeling complex, which was expressed in beta cells during T1D progression in NOD mice and in human beta cells of control, autoantibody-positive, and T1D donors as determined from single-cell RNA-seq data. RNAi knockdown of p21 during senescence in NIT-1 cells did not significantly impact viability or SASP. Taken together, these results suggest that Brd4 interacts with several protein partners during senescence in NIT-1 cells, some of which may play roles in SASP gene activation and that p21 is dispensable for the SASP in this beta cell model. Full article
(This article belongs to the Collection Epigenetic Mechanisms in Diabetes Research)
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30 pages, 2609 KiB  
Review
Impact of Complex Apoptotic Signaling Pathways on Cancer Cell Sensitivity to Therapy
by Ryungsa Kim, Takanori Kin and William T. Beck
Cancers 2024, 16(5), 984; https://doi.org/10.3390/cancers16050984 - 28 Feb 2024
Cited by 25 | Viewed by 8099
Abstract
Anticancer drugs induce apoptotic and non-apoptotic cell death in various cancer types. The signaling pathways for anticancer drug-induced apoptotic cell death have been shown to differ between drug-sensitive and drug-resistant cells. In atypical multidrug-resistant leukemia cells, the c-Jun/activator protein 1 (AP-1)/p53 [...] Read more.
Anticancer drugs induce apoptotic and non-apoptotic cell death in various cancer types. The signaling pathways for anticancer drug-induced apoptotic cell death have been shown to differ between drug-sensitive and drug-resistant cells. In atypical multidrug-resistant leukemia cells, the c-Jun/activator protein 1 (AP-1)/p53 signaling pathway leading to apoptotic death is altered. Cancer cells treated with anticancer drugs undergo c-Jun/AP-1–mediated apoptotic death and are involved in c-Jun N-terminal kinase activation and growth arrest- and DNA damage-inducible gene 153 (Gadd153)/CCAAT/enhancer-binding protein homologous protein pathway induction, regardless of the p53 genotype. Gadd153 induction is associated with mitochondrial membrane permeabilization after anticancer drug treatment and involves a coupled endoplasmic reticulum stress response. The induction of apoptosis by anticancer drugs is mediated by the intrinsic pathway (cytochrome c, Cyt c) and subsequent activation of the caspase cascade via proapoptotic genes (e.g., Bax and Bcl-xS) and their interactions. Anticancer drug-induced apoptosis involves caspase-dependent and caspase-independent pathways and occurs via intrinsic and extrinsic pathways. The targeting of antiapoptotic genes such as Bcl-2 enhances anticancer drug efficacy. The modulation of apoptotic signaling by Bcl-xS transduction increases the sensitivity of multidrug resistance-related protein-overexpressing epidermoid carcinoma cells to anticancer drugs. The significance of autophagy in cancer therapy remains to be elucidated. In this review, we summarize current knowledge of cancer cell death-related signaling pathways and their alterations during anticancer drug treatment and discuss potential strategies to enhance treatment efficacy. Full article
(This article belongs to the Special Issue Feature Review for Cancer Therapy)
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21 pages, 1613 KiB  
Article
The Identification of Nuclear FMRP Isoform Iso6 Partners
by Nassim Ledoux, Emeline I. J. Lelong, Alexandre Simard, Samer Hussein, Pauline Adjibade, Jean-Philippe Lambert and Rachid Mazroui
Cells 2023, 12(24), 2807; https://doi.org/10.3390/cells12242807 - 9 Dec 2023
Cited by 3 | Viewed by 1663
Abstract
A deficiency of FMRP, a canonical RNA-binding protein, causes the development of Fragile X Syndrome (FXS), which is characterised by multiple phenotypes, including neurodevelopmental disorders, intellectual disability, and autism. Due to the alternative splicing of the encoding FMR1 gene, multiple FMRP isoforms are [...] Read more.
A deficiency of FMRP, a canonical RNA-binding protein, causes the development of Fragile X Syndrome (FXS), which is characterised by multiple phenotypes, including neurodevelopmental disorders, intellectual disability, and autism. Due to the alternative splicing of the encoding FMR1 gene, multiple FMRP isoforms are produced consisting of full-length predominantly cytoplasmic (i.e., iso1) isoforms involved in translation and truncated nuclear (i.e., iso6) isoforms with orphan functions. However, we recently implicated nuclear FMRP isoforms in DNA damage response, showing that they negatively regulate the accumulation of anaphase DNA genomic instability bridges. This finding provided evidence that the cytoplasmic and nuclear functions of FMRP are uncoupled played by respective cytoplasmic and nuclear isoforms, potentially involving specific interactions. While interaction partners of cytoplasmic FMRP have been reported, the identity of nuclear FMRP isoform partners remains to be established. Using affinity purification coupled with mass spectrometry, we mapped the nuclear interactome of the FMRP isoform iso6 in U2OS. In doing so, we found FMRP nuclear interaction partners to be involved in RNA processing, pre-mRNA splicing, ribosome biogenesis, DNA replication and damage response, chromatin remodeling and chromosome segregation. By comparing interactions between nuclear iso6 and cytoplasmic iso1, we report a set of partners that bind specifically to the nuclear isoforms, mainly proteins involved in DNA-associated processes and proteasomal proteins, which is consistent with our finding that proteasome targets the nuclear FMRP iso6. The specific interactions with the nuclear isoform 6 are regulated by replication stress, while those with the cytoplasmic isoform 1 are largely insensitive to such stress, further supporting a specific role of nuclear isoforms in DNA damage response induced by replicative stress, potentially regulated by the proteasome. Full article
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16 pages, 3314 KiB  
Article
A New Drug Discovery Platform: Application to DNA Polymerase Eta and Apurinic/Apyrimidinic Endonuclease 1
by Debanu Das, Matthew A. J. Duncton, Taxiarchis M. Georgiadis, Patricia Pellicena, Jennifer Clark, Robert W. Sobol, Millie M. Georgiadis, John King-Underwood, David V. Jobes, Caleb Chang, Yang Gao, Ashley M. Deacon and David M. Wilson
Int. J. Mol. Sci. 2023, 24(23), 16637; https://doi.org/10.3390/ijms242316637 - 23 Nov 2023
Cited by 4 | Viewed by 2861
Abstract
The ability to quickly discover reliable hits from screening and rapidly convert them into lead compounds, which can be verified in functional assays, is central to drug discovery. The expedited validation of novel targets and the identification of modulators to advance to preclinical [...] Read more.
The ability to quickly discover reliable hits from screening and rapidly convert them into lead compounds, which can be verified in functional assays, is central to drug discovery. The expedited validation of novel targets and the identification of modulators to advance to preclinical studies can significantly increase drug development success. Our SaXPyTM (“SAR by X-ray Poses Quickly”) platform, which is applicable to any X-ray crystallography-enabled drug target, couples the established methods of protein X-ray crystallography and fragment-based drug discovery (FBDD) with advanced computational and medicinal chemistry to deliver small molecule modulators or targeted protein degradation ligands in a short timeframe. Our approach, especially for elusive or “undruggable” targets, allows for (i) hit generation; (ii) the mapping of protein–ligand interactions; (iii) the assessment of target ligandability; (iv) the discovery of novel and potential allosteric binding sites; and (v) hit-to-lead execution. These advances inform chemical tractability and downstream biology and generate novel intellectual property. We describe here the application of SaXPy in the discovery and development of DNA damage response inhibitors against DNA polymerase eta (Pol η or POLH) and apurinic/apyrimidinic endonuclease 1 (APE1 or APEX1). Notably, our SaXPy platform allowed us to solve the first crystal structures of these proteins bound to small molecules and to discover novel binding sites for each target. Full article
(This article belongs to the Section Molecular Genetics and Genomics)
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